This invention relates to devices and methods for the treatment tissue. In particular, the treatment involves implantation of angiogenic implants in combination with therapeutic materials such as tissue cells or cell material into injured, diseased or otherwise dysfunctional tissue such as cardiac muscle tissue.
Muscle tissue can become dysfunctional for a variety of reasons. Disease, injury or the effects of surgical intervention all can adversely affect the function of muscle tissue. In many instances tissue becomes dysfunctional due to inadequate blood supply attributable to a variety of causes. Tissue suffering from inadequate blood supply is defined as ischemic tissue. Tissue that is deprived from blood for extended periods of time can become necrotic and permanently non-functioning. Muscle tissue disease can occur anywhere in the body, but commonly occurs in the legs and the heart. Heart disease presents a critical situation to those afflicted and potential treatments to intervene in the disease process of the heart have been the subject of increased study in recent years.
A common approach to treatment of muscle disease has been to treat the subject tissue with pharmacological agents. However, general administration of such agents presents several problems. Typically, agents useful in treating muscle disease are expensive, making general administration through the body relatively costly. Additionally, pharmacological agents can be toxic to other regions of the body, especially when administered in large doses, required to obtain a therapeutically effective concentration at the intended treatment site.
Local delivery of therapeutic agents addresses some of the concerns associated with a therapeutic approach to muscle disease treatment. Delivery of discreet amounts the therapeutic substance directly to the intended treatment site via injection or via a drug delivery catheter navigated to the location offers several benefits. A reduced amount of therapeutic substance can be used because the agent is released only at the intended location and thus is not diluted by its passage throughout the body as occurs with general administration. Also, other areas of the body will not be affected by administration of the substance if it remains only at the intended tissue location. U.S. Pat. No. 5,354,279 (Hofling) discloses a catheter for localized delivery of an agent by injection. However, substances delivered locally do not always remain only at the intended location. Frequently, the substance is not absorbed into the tissue as expected and may be carried away by the bloodstream. Also, even if the substance is injected into the subject tissue as intended, it may be squeezed out of the tissue rapidly rather than being retained for a therapeutically beneficial period of time. This occurrence is especially problematic when treating highly active muscle tissue such as myocardial tissue of the heart because its exaggerated cyclical contraction and relaxation tend to force out locally delivered materials from the intended tissue location.
In recent years treatment of muscular dysfunction with biological therapeutic materials has been a subject of increased study. Stem cells, as well as cell components, such as DNA and proteins, are considered to hold potential as a promising treatment for diseased tissue regions. It has been reported that stem cells may be capable transforming into a highly specialized cells of a given organ in which they are placed. J. Hescheler et al., Embryotic Stem Cells: A Model To Study Structural And Functional Properties In Cardiomyogenesis, Cardiovascular Research 36 (1997) 149-162. Addition of such cells to the tissue of an organ serves to initiate growth of the tissue of that organ. For example such cells may be delivered to regions of diseased tissue of the heart with the expectation that the cells will become cardiomyocytes initiating new cardiac muscle growth to replace the diseased muscle that is present. Precursor cells may also be effective in treating diseased tissue of the heart. R. K. Li et al., Cell Transplantation to Repair Broken Hearts, Can J. Cardiol 1998;14(5): 735:744. Treatment of diseased cardiac tissue by transplanting skeletal myoblast into the subject tissue has also been the subject of recent study. Charles E. Murphy et al., Skeletal Myoblast Transplantation for Repair of Myocardial Necrosis, J. Clin. Invest. 1996 98:2512-2523. However, effective delivery of these biological herapeutic materials is subject to the same concerns discussed above in connection with delivery of pharmacological therapeutic materials. Specifically, biological therapeutic materials can be ejected from the intended muscle location by movement of the muscle, prior to any ameliorative effect the cells may bring to the area.
Biological therapeutic materials present an additional challenge in order to be delivered effectively in that their metabolic activity must be sustained while they are implanted so that they remain viable and capable of carrying out their intended function. The biological materials require a blood supply that carries nutrients to sustain their viability. However, an adequate supply of blood is typically unavailable at the site of diseased tissue where such biological materials would be applied. This is especially true in regions that are ischemic.
It would be desirable to provide a muscle tissue treatment that effectively delivers therapeutically beneficial materials to an intended tissue location while addressing the above-mentioned challenges to effective delivery of a therapeutic material. It is an object of the present invention to provide devices and methods for treating muscle dysfunction that address those concerns.
The present invention provides devices and methods for diseased tissue such as muscle tissue that has become dysfunctional due to disease. The devices and methods are intended to be useful in any tissue of the human body. However, the invention is believed to be particularly useful in the treatment of heart muscle that has become damaged or dysfunctional because of disease, ischemia or other injury. The treatment comprises implantation into subject tissue of an angiogenic implant device in combination with therapeutic material associated with the device. Though the angiogenic device may have pharmacological agents associated with it, biological materials such as tissue, cells or cell material are believed to be particularly well suited for combination with the device because the device will serve as a scaffold holding them in place in the host tissue and will initiate angiogenic activity that will serve to supply the biological materials with needed blood.
Therapeutic materials are considered to comprise cells or, groups of cells forming tissue. Examples of therapeutic cells are stem cells, myoblasts, cardiomyocytes, or precursor cells or genetically engineered cells potentially useful in the treatment of tissue disease, ischemia and necrosis that may occur anywhere in the human body. In particular, ailments that afflict myocardial muscle tissue are addressed by the present invention. Therapeutic materials may also include growth factors or cell components such as genes or DNA. It is also recognized that inhibitors such as tumor necrosis factors may be delivered by the devices and methods of the present invention for controlling undesirable tissue growth such as that of tumors. Such treatment is also to be considered within the scope of the invention.
The angiogenic implants utilize the body""s own healing process to induce angiogenesis and recruitment of existing vessels to the implant site. Vessel growth and recruitment is believed to be initiated by injury or aggravation of the tissue in which the device has been implanted. Fibrin created during the tissue""s injury response may additionally help to promote angiogenesis because its fibrous network provides a host structure for endothelial cells, which will form the new blood vessels to the area. Additionally, thrombin that has been produced and remains in the fibrin network serves to direct the endothelial cells to migrate and proliferate so that new vessels are formed to the fibrin area.
As mentioned above, the present invention is intended to be useful in any muscle tissue of the body that has become damaged or suffers reduced function. For example, the legs commonly suffer from reduced blood flow that leads to ischemia of the muscle tissue in those regions. Also, restricted blood flow to the heart tissue commonly caused by blocked coronary arteries often results in ischemia that causes severe chest pain. Ischemic tissue can become infarcted and necrotic if left untreated. The present invention is well suited to treat such ailments. It is emphasized, however, that the devices and methods herein disclosed are applicable to any area of body tissue in which it is desirable to promote muscle tissue repair. Furthermore, multiple devices can be implanted, or procedures performed, to treat a region of tissue.
The angiogenic implant comprises a device that is implanted into tissue and is configured to promote angiogenesis in the subject tissue. The angiogenic implant device may be formed in a variety of configurations, but should comprise a structure, scaffold or frame, flexible or rigid, having a region where the therapeutic material may be fostered and retained in association with the implant device, in, on, or around its structure. The retention region may be on the interior or exterior of the device. However, the device should be configured to permit communication between the associated therapeutic material and the surrounding tissue into which the device has been implanted. Blood, carrying nutrients must be permitted to flow to and from the therapeutic materials, if they are biological in nature, such as tissue, cells or cell material, so that the metabolic activity of the biological structures is sustained for a therapeutically effective time. After implantation of the angiogenic implant, new and recruited blood vessels will grow to the area of the implant site to supply the therapeutic materials with nutrients.
The therapeutic material should be securely associated with the angiogenic implant. If the material is retained in an interior chamber of a device, openings between the interior and exterior of the device should be present to permit blood to reach the material. If the device is configured to maintain the therapeutic material on its exterior, the material should be formed to the surface, adhered the device or retained in a matrix that can be adhered to the device, such as a polymer matrix.
The device and associated material should be securely anchored in the tissue to prevent migration from the tissue. Therapeutic material such as tissue, cells or cell material may tend to migrate when placed in active muscle tissue such as the myocardium. Cyclic contraction and relaxation of surrounding tissue can serve to push the material out of the muscle. The implant device provides a scaffold structure to hold the moving tissue back so as not to squeeze out the implanted therapeutic material. Additionally, the implant device should be scanned in its position in the tissue. Anchoring may, but need not, involve a dedicated component on the angiogenic implant device such as a projection that claws into surrounding tissue.
Anchoring also may be accomplished by configuring the device to have an overall shape that resists movement through the tissue. Furthermore, the method of delivery and placement of the device in the tissue may insure sufficient anchoring to prevent migration, without a specific anchor structure being associated with the device.
The angiogenic implant devices are preferably configured to cause some injury and irritation to surrounding tissue. Injury triggers a healing response in tissue leading to angiogenesis and vessel recruitment. Therefore, a device configured to cause injury while implanted helps to initiate and sustain the injury response and resulting vessel growth. The device may be configured to irritate the tissue, either biologically or mechanically. A number of agents may be applied to the device to cause an adverse biological reaction in surrounding tissue or the device maybe formed of material that irritates tissue, such as a polymer. Mechanical irritation may be accomplished by configuring the device to have surfaces that irritate tissue, such as protrusions. The surfaces of the device serve to slightly injure the tissue during frictional contact between device and surrounding tissue. The frictional contact with the tissue occurs not only during implantation, but also, when muscle tissue thereafter relaxes and contracts.
The angiogenic implant devices are scaffold structures. They may be solid structures or may be hollow and define an interior chamber. Hollow structures may include, for example, mesh tubes, coils or capsules. Regardless of the exact configuration of a hollow device, if the interior chamber is intended to hold the therapeutic material, it should be in communication with tissue that surrounds the implanted device. For example, pores or openings through the surface of the device should be present so that blood carrying nutrients can flow between the interior chamber and exterior of the device.
The devices may be permanent or biodegradable. Also, the devices may have associated with them substances that promote angiogenesis, such as growth factors, separate from the therapeutic material intended to treat the muscle dysfunction. In the case of biodegradable implants, the therapeutic material may be embedded in the biodegradable material so as to be released during the degradation of the biodegradable material. By this arrangement, the therapeutic material is released gradually into the surrounding tissue. In the case of permanent implants, therapeutic materials may be applied by coating the surfaces of the device with the material or with a composition that serves to host the material. The material is released from the coating of the device over time as the coating dissolves or as blood gradually carries it away from the coating matrix. Therapeutic material may also be adhered to the implant by surgical adhesive or by collagen. In the case of hollow implants having an interior chamber, the therapeutic material may be inserted into the chamber during delivery and is retained with in the cavity by the device and surrounding tissue without being attached to a particular surface of the device.
Another method of associating therapeutic material with the angiogenic implant is by loading the material in a thrombus formed from blood previously removed from the body. The thrombus may be formed within the interior chamber of a hollow device ex vivo or preformed ex vivo first, then placed into the interior prior to or during implantation. In the case of a solid device, the thrombus may be permitted to form around the exterior of the device ex vivo before it is implanted in tissue. In addition to providing a host matrix for the therapeutic material, the formed thrombus may hasten revascularization in the subject tissue by providing a ready made completed fibrin network into which growth factors and endothelial cells may be attracted. Also, the formed thrombus could be preloaded with growth factors or other agents, thereby serving as a natural, biodegradable host network for the angiogenic agents.
Tumors may also be treated with the devices and methods of the present invention. However rather than being configured to promote tissue and vessel growth as with the devices described above, a tumor implant is configured to inhibit growth of the tumor tissue and, preferably, is configured to kill the tumor tissue. For tumor treatment, the implant device is configured to be implantable in a tumor and configured to hold biological material that is lethal to the tumor cells, such as a tumor necrosis factor. The implant provides the important function of retaining the tumor necrosis factor in the tumor so that it does not migrate to other areas of the body to cause harm to healthy tissue.
It is an object of the present invention to provide devices and methods to stimulate muscle function.
It is another object of the invention to provide a reliable treatment for heart muscle disease and dysfunction whereby cell therapy is employed in combination with an implant device.
It is another object of the invention to provide an implant device configured to sustain and retain therapeutic material such as cells in host tissue.
It is another object of the invention to provide a method of treating biological tissue by delivering a scaffold implant device in combination with a therapeutic material.
It is another object of the invention to provide a method of supplying blood and nutrients to a biological therapeutic material placed in tissue by delivering an angiogenic implant to the tissue site.
It is another object of the invention to provide treatment for muscle dysfunction that is safe and reliable for the patient.
It is another object of the invention to provide a method and device for treating a tumor by combining an implant device with a biological material configured to inhibit tumor growth.